Metolazone, 7-chloro-1,2,3,4-tetrahydro-2-methyl-3-(2-methylphenyl)-4-oxo-6-quinazolin esulfonamide, is a potent antihypertensive and diuretic drug. Metolazone is a diuretic structurally related to quinethazone but has a greater potency, on a weight basis, than either quinethazone or hydrochlorothiazide. Metolazone is commonly available in oral dosage forms. Particularly in critical care situations such as for treatment of refractory edema or renal failure, a more desirable form of the drug is as an injectable solution. Aqueous solutions are preferred for intravenous administration, however, metolazone has very low solubility in water (about 0.02 mg/ml).
One approach to produce aqueous solutions of metolazone has been to increase the pH of the solution by the addition of, for example, alkali hydroxides. An aqueous solution having a pH of about 11 is sufficient to solubilize metolazone. However, such a high pH is undesirable for use in parenteral administration due to pain and irritation at the site of injection and possible precipitation of the metolazone. Moreover, metolazone is chemically unstable at this high pH. An example of using a high pH to solubilize metolazone is found in the work of Vasant Ranade (U.S. Pat. Nos. 5,633,240, 5,684,009, and 5,814,623). The highest concentration of metolazone achieved without precipitation was 2 mg/ml, and even this concentration usually resulted in precipitation. See Tables 1 and 2 of any of the Ranade patents. The preferred solutions in the Ranade patents contain about 1 mg/ml of metolazone. See U.S. Pat. No. 5,633,240 at column 2, lines 51 to 53.
Various other solutions to the problem of low metolazone solubility have been suggested in the art. Combining metolazone with other drugs to increase its effectiveness has been suggested. The formation of aqueous solutions containing various solvents and metolazone has also been reported. For example, aqueous metolazone solutions containing propylene glycol and ethyl alcohol have been produced in, for example, U.S. Pat. No. 5,124,152 (Biringer et al.). This patent exemplifies aqueous metolazone solutions having concentrations up to 4.25 mg/ml, and these solutions include some having a cosolvent of propylene glycol and ethyl alcohol. The '152 patent claims an aqueous metolazone solution having a concentration from 0.1 to 8 mg/ml of metolazone. The apparent equilibrium solubility limit of metolazone in an aqueous solution of 65% w/v propylene glycol, 15% w/v ethyl alcohol is approximately 8 mg/ml. See below. FIG. 1 of the '152 patent demonstrates that certain solutions can be formed using metolazone, ethyl alcohol, and propylene glycol. These solutions were formed by mixing the metolazone with the propylene glycol/ethyl alcohol mixture and then adding water. No heating was used. The metolazone in the solution shown in FIG. 1 of the '152 patent was above its apparent equilibrium solubility limit below about 2 mg/ml.
With some metolazone solutions containing organic solvents, there can be problems of irritation or precipitation of the drug at the site of injection. Thus, it is desirable to administer as low a total volume of the injectable solution as possible in order to minimize the side effects due to non-aqueous solvents. It is also desirable to prevent precipitation upon intravenous injection as it can result in reduced bioavailability of the drug, pain upon injection, or phlebitis.
Precipitation at the site of drug injection is related to the solubility of the drug in biological fluids. The rate of administration of a solution of a drug determines the degree of dilution in biological fluids and whether the solubility of the drug in the mixture of fluids will be exceeded. Normally one would expect that if the concentration of the drug at the site of injection exceeds the solubility of the drug in the biological fluid, precipitation would occur.
The present invention provides a method to make parenteral metolazone formulations in which the concentration of metolazone is much higher than any that have been previously proposed for parenteral formulations. In fact, the concentration of metolazone is above the apparent equilibrium solubility of metolazone in the solution. Because the concentration of metolazone is high, the amount of non-aqueous solvent per dose that must be introduced into the patient is lower than earlier formulations. Because less non-aqueous solvent is introduced into the patient, there should be less irritation at the site of injection. These solutions of metolazone also would be expected to not precipitate upon intravenous injection.
The method of making the parenteral metolazone formulations involves adding metolazone to a solvent other than water so that a high concentration of metolazone is dissolved in the solvent. In a preferred embodiment, the metolazone and solvent other than water are heated, the solution is cooled, and other solvents are added. The method results in solutions of metolazone that can remain stable for a long period of time. The solutions of the invention have much higher concentrations of metolazone than any previously reported solutions of metolazone that exceeded their apparent equilibrium solubility.